Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells.

BACKGROUND & AIMS: Hepatocellular carcinoma is a common complication in liver cirrhosis. The integrin alpha6 beta1, a receptor for the laminin family of extracellular matrix proteins, has been found to be overexpressed in hepatocarcinoma. In an effort to further characterize the involvement of alpha6 beta1-integrin in hepatocarcinoma progression and to study alpha6 beta1-mediated functions, a human hepatocarcinoma cell line, HepG2, that express high surface levels of alpha6 beta1 and uses only this integrin to mediate adhesion on laminin was identified. METHODS: To assess the role of alpha6 beta1 in these cells, a cytoplasmic domain deletion mutant of the beta4-integrin subunit by complementary DNA transfection was expressed. The expression of the mutant beta4 subunit in association with endogenous alpha6 showed a dominant-negative effect on alpha6 beta1 expression. RESULTS: Stable transfectants of HepG2 that expressed the mutant beta4 subunit showed a reduced ability to adhere and migrate on laminin matrices and to invade Matrigel. Furthermore, transfected cells showed significantly lower growth rates and reduced anchorage-independent growth compared with mock-transfected cells. CONCLUSIONS: These findings on the expression and function of alpha6 beta1 in hepatocarcinoma cells emphasize the potential contribution of this laminin receptor in the neoplastic transformation of hepatocytes.

[Role of the liver in the regulation of glucose metabolism in diabetes and chronic liver disease]. / Ruolo del fegato nella regolazione del metabolismo glucidico in corso di diabete e di epatopatia cronica.

The liver plays a major role in the regulation of glucose metabolism: plasma glucose concentration is the result of peripheral glucose utilization and liver production. Several hormones, including insulin, glucagon, growth hormone, cortisol, and catecholamines contribute to the regulation of glucose metabolism by the liver. In this review, we examine hepatic glucose metabolism, in particular the actions of insulin and contrainsular hormones on glucose hepatic uptake and production in patients with diabetes or chronic liver disease. The most frequent patterns of hepatic involvement that take place during diabetes, i.e. nuclear glycogenesis, steatosis, portal fibrosis, and diabetic steatonecrosis, are discussed. Also considered are anomalies of glucose homeostasis observed in chronic liver disease, including glucose intolerance, diabetes, and hypoglycemias. There is a strong correlation between diabetes mellitus and the liver: diabetic patients have typical histological lesions, while several glucose metabolism alterations are commonly found in subjects with chronic liver disease. The pathogenesis of impaired glucose metabolism during chronic liver disease has not yet been fully understood: further clinical and experimental studies should clarify this issue.

Pharmacokinetics and pharmacodynamics of torasemide and furosemide in patients with diuretic resistant ascites.

BACKGROUND/AIM: To evaluate the pharmacokinetics and pharmacodynamics of furosemide and torasemide in patients with cirrhosis and diuretic resistant ascites. METHODS: Eighteen patients were randomly allocated to receive intravenous torasemide (40 mg) or furosemide (80 mg). The renal response to these drugs was assessed in baseline conditions and in the 24 h following drug administration together with plasma and urinary concentrations of furosemide, torasemide and its metabolites. RESULTS: Torasemide induced significantly greater diuretic and natriuretic effects than furosemide in the first hour after drug administration. No other significant differences between the two drugs were observed with respect to the renal response to these drugs. Torasemide reached a lower maximum plasma concentration than furosemide, but the former drug had a longer apparent terminal half-life and lower renal and non-renal clearances. Comparing these results with those previously reported in healthy subjects, both drugs showed a reduced elimination rate through renal and non-renal routes, and a larger distribution to body fluids. As a consequence, the half-life of both drugs was longer than in healthy subjects. Urinary excretion of pharmacologically active species, however, was quantitatively unchanged after torasemide administration, whereas it was reduced after furosemide. Finally, the natriuretic potency of both drugs was markedly reduced in these patients. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of torasemide and furosemide are markedly altered in patients with diuretic resistant ascites.

Thyroxine-binding globulin in elderly patients with hepatocellular carcinoma.

In order to evaluate the possible relevance of the increased serum levels of thyroxine binding globulin (TBG) in elderly patients with cirrhosis and hepatocellular carcinoma (HCC), TBG and alpha-fetoprotein (AFP) levels were measured in 3 groups: (i) 14 healthy subjects (mean age: 74 +/- 2 years); (ii) 15 patients with cirrhosis of the liver (mean age: 70 +/- 1 years); (iii) 17 patients with cirrhosis and HCC (mean age: 71 +/- 1 years). Both TBG and AFP levels were significantly higher (p < 0.01) in the patients with HCC, as compared to the healthy subjects or to the cirrhotic ones without HCC. The increased plasma TBG levels in cirrhotic patients with HCC is probably due to a derepression of the TBG gene in hepatocytes undergoing neoplastic transformation. The results suggest that TBG together with AFP may be of diagnostic value for the presence of HCC in aging patients with liver cirrhosis.

[Obesity: a multifactorial disorder with difficult long-term treatment]. / Obesità: malattia multifattoriale di difficile trattamento a lungo termine.

Obesity is a social disease and amounts to a real medical problem. After considering its epidemiology, the authors discuss diagnostic methods, etiopathogenesis, clinical features, complications, and management of obesity. Special stress is laid upon particular problems concerning the causes of obesity which are often difficult to identify, and difficulties of long-term treatment. Thus it becomes obvious that the disorder must be prevented, and maximum attention must be placed on renewed weight increase.

[Osteoporosis. The recent findings on its etiopathogenesis, diagnosis and therapy. II. Therapy]. / Osteoporosi. Recenti acquisizioni in tema di etiopatogenesi, diagnosi e terapia. Parte II. - Terapia.

Management of osteoporosis has as yet a number of aspects that are not well understood and at times even contradictory, also in view of the fact that some physicians have their "personal therapeutic approach". While on the one hand, the US FDA recognizes calcium, estrogens and calcitonin as the sole remedies for osteoporosis, on the other a variety of drugs have been studied and are at present in use. Among the drugs considered are those apt to reduce bone resorption (calcium, vitamin D metabolites, estrogens, calcitonin, diphosphonates, and ipriflavone) and those favouring bone formation (fluorides, anabolic androgens, PTH and ipriflavone). In addition, future approaches to osteoporosis therapy are considered which may make use of anti-interleukin 1 and 6, as well as of growth factors with specific osteotropism. At present, the physician must know what types of treatment are available for the individual patient with osteoporosis and be able to evaluate the cost/benefit ratio of each drug together with its side effects.

[Osteoporosis. Current advances in etiopathogenesis, diagnosis and therapy. I.--Etiopathogenesis and diagnosis]. / Osteoporosi. Recenti acquisizioni in tema di etiopatogenesi, diagnosi e terapia. Parte I.--Etiopatogenesi e diagnosi.

Throughout life, bone is a tissue continuously remodelled with processes of bone formation followed by resorption. Osteoporosis, a social disease, is characterized by an unbalance of these processes with prevalence of resorption over neoformation. Numerous risk factors may cause or favour this disease. The classification of different types of osteoporosis is presented and the etiopathogenesis and clinical pattern of involutional and secondary osteoporosis are described. We have at our disposal a variety of diagnostic procedures which are also useful for prevention and management.

Circadian variations of plasma somatostatin levels in healthy subjects.

The plasma levels of somatostatin-like immunoreactivity, growth hormone and insulin were measured using a RIA method in healthy volunteers every 4h during the day and every 2h at night, without waking the subjects. In the waking state the fluctuation of plasma somatostatin-like immunoreactivity level only occurred near to meal time. A marked episodic surge of plasma SLI (peak value, 127.25 +/- 4.40 pg/ml (mean +/- ES)) was noted at 0200 in the initial period of slow wave sleep (SWS) 2h after the peak of GH. Insulin showed no sharp peak and its pattern was unrelated to other two hormones studied. A positive correlation was observed between SLI and GH in plasma using the mean cosinor method: the acrophase of SLI was at 0018 about 1h later than GH (at 2315). The acrophase of insulin occurred at 1525, significantly different as compared with the previous two. From these findings, it is concluded that SLI in peripheral plasma fluctuates with a significant circadian rhythm and a nychthemeral maxima as GH and that, whatever its source, that it is related to plasma GH and not to plasma insulin.

Estimate of prevalence of glucose intolerance in chronic liver disease. Degree of agreement among some diagnostic criteria.

In patients with chronic liver disease, the reliability of various criteria generally used to diagnose impaired glucose tolerance and diabetes was evaluated. Twenty-one patients with chronic persistent hepatitis, 68 patients with chronic active hepatitis and 57 patients with liver cirrhosis were studied. All subjects underwent an oral glucose tolerance test (75 g). Impaired glucose tolerance and diabetes were diagnosed according to the criteria established by: the National Diabetes Study Group; Fajans and Conn; the European Diabetes Study Group; Deutsche Diabetes Gesellschaft; Kobberling & Creutzfeld criteria 1 and 2; Wilkerson; and the University Group Diabetes Program. The results obtained are in partial agreement with other reported data, showing a high prevalence of both impaired glucose tolerance and diabetes in chronic liver disease, with a positive correlation to the severity of hepatic involvement. However, our results show that the agreement among the criteria most frequently used for diagnosing impaired glucose tolerance and diabetes is still far from satisfactory.